Milić Patrik, Kjuder Mojca Justin, Gradišar Katerina Jazbec, Švajger Urban, Rožman Primož
Slovenian Institute for Transfusion Medicine, Šlajmerjeva ulica 6, Ljubljana, SI-1000, Slovenia.
The Faculty of Medicine, University of Ljubljana, Vrazov trg 2, Ljubljana, SI-1000, Slovenia.
Immun Ageing. 2025 Jul 3;22(1):26. doi: 10.1186/s12979-025-00517-9.
Aging is linked to various dysfunctions of the immune system, including the decline of its primary developmental source: the hematopoietic stem cell (HSC) niche. This decline leads to chronic inflammation, increased vulnerability to infections, cancer, autoimmune diseases, and reduced vaccine efficacy. As individuals age, the HSC niche undergoes significant changes, including greater adipocyte accumulation and alterations in the molecular microenvironment, which may influence the development and function of immune cells. Among these cells, the impact of the aging HSC niche on dendritic cell (DC) function is less understood. Heterochronic autologous HSC transplantation is a promising intervention to prevent age-related disorders, contributing to the extension of healthspan and longevity, however, several murine experiments failed to produce the expected results, which led us to presume that the problem lies within the old HSC niche. Therefore, we created in vitro models of young and old HSC niches and examined how these microenvironments affect the differentiation and maturation and functionality of BM-derived DCs (BMDCs).
An analysis of the conditioned media from young and aged HSC niches revealed that the environment of aged niches exhibited an increased presence of adiponectin. This media was subsequently utilized in BMDC differentiation and maturation protocols, with their effects closely monitored. Our results indicate that the old HSC niche microenvironment promotes premature BMDC activation, characterized by elevated MHC class II expression and enhanced allostimulatory capacity of BMDCs at their immature stage. Additionally, LPS stimulation of BMDCs, used to induce DC maturation, significantly increased CD86 expression on BMDCs from the aged niche. However, these cells did not show superior allostimulatory capacity compared to their counterparts from the young niche environment. By analyzing the BMDC cytokine profile, we observed that when cultured in aged niche-conditioned media, the BMDCs secreted significantly higher levels of IL-6, indicating a heightened proinflammatory activation state.
Collectively, our findings suggest that aging-related changes within the HSC niche can considerably alter DC functionality by disrupting their normal development from BM precursors. These results emphasize the significance of this phenomenon and its implications for immunosenescence.
衰老与免疫系统的各种功能障碍有关，包括其主要发育来源——造血干细胞（HSC）微环境的衰退。这种衰退会导致慢性炎症、对感染、癌症、自身免疫性疾病的易感性增加，以及疫苗效力降低。随着个体年龄的增长，HSC微环境会发生显著变化，包括脂肪细胞积累增加和分子微环境改变，这可能会影响免疫细胞的发育和功能。在这些细胞中，衰老的HSC微环境对树突状细胞（DC）功能的影响尚不清楚。异时自体HSC移植是一种有前景的预防与年龄相关疾病的干预措施，有助于延长健康寿命和寿命，然而，一些小鼠实验未能产生预期结果，这使我们推测问题出在旧的HSC微环境中。因此，我们创建了年轻和年老HSC微环境的体外模型，并研究了这些微环境如何影响骨髓来源的DC（BMDC）的分化、成熟和功能。
对年轻和年老HSC微环境的条件培养基分析表明，年老微环境中脂联素的含量增加。随后将这种培养基用于BMDC的分化和成熟方案，并密切监测其效果。我们的结果表明，年老的HSC微环境促进BMDC过早激活，其特征是未成熟阶段的BMDC的MHC II类表达升高和同种异体刺激能力增强。此外，用于诱导DC成熟的LPS刺激显著增加了来自年老微环境的BMDC上的CD86表达。然而，与来自年轻微环境的对应细胞相比，这些细胞并未表现出更高的同种异体刺激能力。通过分析BMDC细胞因子谱，我们观察到，当在年老微环境条件培养基中培养时，BMDC分泌的IL-6水平显著更高，表明促炎激活状态增强。
总体而言，我们的研究结果表明，HSC微环境中与衰老相关的变化可通过破坏BM前体细胞的正常发育而显著改变DC功能。这些结果强调了这一现象的重要性及其对免疫衰老的影响。
